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1、This journal is The Royal Society of Chemistry 2022Chem.Soc.Rev.Cite this:DOI:10.1039/d1cs00307kActivity-based NIR fluorescent probes based onthe versatile hemicyanine scaffold:designstrategy,biomedical applications,and outlookThe discovery of a near-infrared(NIR,650900 nm)fluorescent chromophore he
2、micyanine dye with highstructural tailorability is of great significance in the field of detection,bioimaging,and medical therapeutic appli-cations.It exhibits many outstanding advantages including absorption and emission in the NIR region,tunablespectral properties,high photostability as well as a
3、large Stokes shift.These properties are superior to those ofconventional fluorogens,such as coumarin,fluorescein,naphthalimides,rhodamine,and cyanine.Researchershave made remarkable progress in developing activity-based multifunctional fluorescent probes based onhemicyanine skeletons for monitoring
4、vital biomolecules in living systems through the output of fluorescence/photoacoustic signals,and integration of diagnosis and treatment of diseases using chemotherapy orphotothermal/photodynamic therapy or combination therapy.These achievements prompted researchers todevelop more smart fluorescent
5、probes using a hemicyanine fluorogen as a template.In this review,we beginby describing the brief history of the discovery of hemicyanine dyes,synthetic approaches,and design strategiesfor activity-based functional fluorescent probes.Then,many selected hemicyanine-based probes that candetect ions,sm
6、all biomolecules,overexpressed enzymes and diagnostic reagents for diseases are systematicallyhighlighted.Finally,potential drawbacks and the outlook for future investigation and clinical medicinetransformation of hemicyanine-based activatable functional probes are also discussed.aState Key Laborato
7、ry of Fine Chemicals,Dalian University of Technology,2 Linggong Road,Dalian 116024,China.E-mail:bSchool of Bioengineering,Dalian University of Technology,2 Linggong Road,Dalian 116024,ChinacDepartment of Chemistry and Nano Science,Ewha Womans University,Seoul 03760,Korea.E-mail:jyoonewha.ac.krdThe K
8、ey Laboratory of Laboratory Medicine,Ministry of Education,School of Laboratory Medicine and Life Science,Wenzhou Medical University,Wenzhou 325035,ChinaeSchool of Chemical and Biomedical Engineering,Nanyang Technological University,70 Nanyang Drive,637457,Singapore.E-mail:kypuntu.edu.sgfDivision of
9、 Chemistry and Biological Chemistry,School of Physical and Mathematical Sciences,Nanyang Technological University,21 Nanyang Link,SingaporegResearch Institute of Dalian University of Technology in Shenzhen,Nanshan District,Shenzhen 518057,ChinaHaidong LiHaidong Li obtained his PhD fromDalian Univers
10、ity of TechnologyunderthesupervisionofProf.XiaojunPengin2019.Then,hejoinedtheDepartmentofChemistry and Nanoscience,EwhaWomansUniversity,wherehewasapostdoctoral fellow in the group ofProf.Juyoung Yoon.Now,he is anassociate professor in the School ofBioengineering at Dalian Universityof Technology.His
11、 research interestis focused on activatable bioprobesand theranostic agents.Heejeong KimHeejeong Kim obtained her BScfrom Ewha Womans University in2020.Currently,she is pursuing herPhD degree under the supervision ofProf.JuyoungYoonatEwhaWomans University.Her researchinterestisfocusedonsupra-molecul
12、ar nano-agents and AIEtheranostic agents.These authors contributed equally to this work.Received 11th November 2021DOI:10.1039/d1cs00307krsc.li/chem-soc-revChem Soc RevREVIEW ARTICLEPublished on 10 February 2022.Downloaded by Dalian University of Technology on 2/21/2022 6:42:33 AM.View Article Onlin
13、eView JournalChem.Soc.Rev.This journal is The Royal Society of Chemistry 20221.IntroductionThe monitoring of ions,active biomolecules,and vital enzymesin the physiological and pathological processes of living cellsand in vivo by using optical probes has significance for thediagnosis and treatment of
14、 diseases.124At present,the designand development of molecular imaging probes,especially thosewith emission in the near infrared region(NIR,650900 nm),isa relatively hot research field in chemical biology,biomedicineand molecular biology.2531In particular,activity-based NIRfluorescent probes have ga
15、ined attention due to their outstandingadvantages in the field of detection and bioimaging.3234Theseadvantages include high specificity,good sensitivity,deep tissuepenetration as well as a high signal-to-noise ratio,which caneffectively prevent false positive signals.35However,due to thelack of an i
16、deal fluorophore platform,smart NIR fluorescentprobes are very challenging to fabricate.Therefore,innovativestrategies are being sought to develop a new fluorophore.As far as we know,traditional fluorophores including coumarin,naphthalimide,and fluorescein have been widely used toconstruct functiona
17、l probes for the detection of importanttargets in living cells(such as H2S,H2O2,and enzymes)for thepast several decades,because their hydroxyl groups can bedecorated to control their optical properties.3644Unfortunately,the properties of absorption and emission in the visible regiongreatly limit the
18、ir application in in vivo imaging.The NIRfluorescent probes employed for in vivo imaging mostly belongto the cyanine dye family.45Over the last few decades,lots ofcyanine-based fluorescent probes have been developed for bio-imaging through nucleophilic substitution in chloro-substitutedcyanine dye d
19、erivatives.4548However,the performance ofcyanine fluorophores still needs to be improved.For instance,highly conjugated cyanine dyes are vulnerable to chemicaldestruction by nucleophiles or oxidants.49,50Additionally,thefluorescence behaviors of cyanine-based probes are difficult toquench by a photo
20、induced electron transfer(PET)mechanismbecause of their high-lying occupied molecular orbital(HOMO)energy levels.51,52Subsequently,many researchers have made great efforts todevelop alternative fluorophores with superior performance.As a milestone,Lin et al.discovered a new class of NIRhemicyanine f
21、luorophores(named HDs)by accidently treatingchloro-substituted cyanine dyes with resorcin.53HDs providean excellent platform for the construction of activity-based NIRactivatable bio-probes.They have hydroxyl functional groupsthat regulate the fluorescence behaviors in the near infraredregion(Fig.1A
22、),allowing for the detection and imaging oftargets in vivo with high signal-to-noise ratio.54Subsequently,Feng XuFeng Xu obtained his PhD(2020)from Dalian University of Tech-nology under the supervision ofProf.Xiaojun Peng.Currently,he isworking as a research assistant atWenzhou Medical University.H
23、isresearchinterestisfocusedoncyanine dyes for tumor imagingand therapy.Jingjing HanJingjing Han obtained her mastersdegree(2019)from the University ofChinese Academy of Sciences underthe supervision of Prof.Xuehai Yan.Now she is pursuing her PhD degreeunderthesupervisionofProf.Juyoung Yoon at Ewha W
24、omansUniversity.Her research interest isfocused on activatable fluorescentprobes,supramolecularnano-agents,and AIE theranostic agents.Qichao YaoQichao Yao obtained his BS fromHuazhong University of Science andTechnology(HUST),MDfromZhejiang Science-Technology Uni-versity(ZSTU)andPhDfromDalian Univer
25、sity of Technology(DLUT)under the supervision ofProf.Xiaojun Peng in 2019.Nowhe is a postdoctoral fellow at StateKey Laboratory of Fine ChemicalsfellowProf.JiangliFan.Hisresearchinterest is focused on visualizationof life processes as well as tumordiagnosis and treatment.Jingyun WangJingyun Wang is
26、a professor in theSchool of Bioengineering at DalianUniversityofTechnology.Shereceived her PhD(2001)fromDalian University of Technologyand conducted her postdoctoralwork at Northwestern University(USA).Herresearchinterestsinclude fluorescent probes,drug/gene delivery smart nanomaterials,and multifun
27、ctional nanomaterialsfor diagnosis and treatment ofdiseases.Review ArticleChem Soc RevPublished on 10 February 2022.Downloaded by Dalian University of Technology on 2/21/2022 6:42:33 AM.View Article OnlineThis journal is The Royal Society of Chemistry 2022Chem.Soc.Rev.the protection and deprotection
28、 strategy of hydroxyl groups ofhemicyanine fluorophores has been employed to design andconstruct activatable fluorescent probes to meet the requirementsof in vitro detection and life science research.5560Later,somederivatives of hemicyanine fluorophores were fabricated by chan-ging the electron-with
29、drawing groups(EWG)or electron-donatinggroups(EDG).Representative derivatives(16)of NIR fluorophoreHDs are shown in Fig.1B.Using an amino-substituted hemi-cyanine dye(X=NH2),Ma and colleagues devised some elegantenzyme-activatableNIRfluorescentprobesforimagingtumors.6163Yuan et al.designed dual poly
30、prodrugs of thehemicyanine dye and doxorubicin to form a time-programmedactivation nanosystem for efficient synergistic cancer therapy.64Additionally,heavy atom(e.g.,iodine and bromine)substitutedhemicyanine dyes were used by Peng,Zhang,and Patsenker foranti-bacterial applications and for killing tu
31、mors.6568The groupof Pu designed and developed some smart macromoleculardiagnostic reagents for biomedical application.14,6973Morerecently,Chans and Shens groups independently reportedenhanced photoacoustic probes for the detection of analytes bythe substitution of oxygen atoms of typical hemicyanin
32、e fluoro-phores with sulfur atoms.74,75Intriguingly,Ma and co-workersadopted a molecular-splicing strategy to construct a novel hydroxylhemicyanine fluorophore derivative in fluorescence-off state thatcould be applied to monitor phase II metabolic enzymes with aturn-on signal.76Several reviews about
33、 cyanine scaffold probes have beenpublished that are just related to independent probes foroptical imaging of small molecules and drug delivery.31,45,77,78However,to the best of our knowledge,there is no comprehensiveand specific review of activity-based NIR hemicyanine probesdescribing their design
34、 strategies,preparation,bioimaging,anduse in diagnosis and therapy of diseases.In recent years,manyimportant advances in hemicyanine probes have been made foractivatable fluorescence/photoacoustic imaging combined withKanyi PuKanyi Pu is an Associate Professorin the School of Chemical andBiomedicalE
35、ngineeringatNanyang Technological University.He obtained his PhD(2011)fromthe National University of Singaporein Singapore.Then,he moved toStanfordUniversitySchoolofMedicineforhispostdoctoralstudy.Heisahighlycitedresearcher,Fellow of the RoyalSociety of Chemistry(FRSC),andtheassociateeditorforACSApp
36、lied Polymer Materials andBiomaterials Research,and Young Star Editor of Nano Research.His research interests include activatable molecular optical probesand semiconducting polymer nanomaterials for bioimaging anddisease diagnosis.Xiaojun PengXiaojun Peng is currently professoranddirectorattheStateK
37、eyLaboratoryofFineChemicals,Dalian University of Technology.He earned his PhD(1990)fromDalian University of Technologyandconductedhispostdoctoralwork at Nankai University.In 2001and 2002,he was a visiting scholaratStockholmUniversityandNorthwestern University(USA).Hisresearch interests cover fluores
38、centdyesforbioimaging/biolabeling,digitalprinting/recording,andphotochemistry of supramolecules.Juyoung YoonJuyoung Yoon is a distinguishedprofessorattheDepartmentofChemistry and Nanoscience,EwhaWomans University.He received hisPhD(1994)fromOhioStateUniversityandconductedhispostdoctoral work at UCLA
39、 andScrippsResearchInstitute.Hisresearch interests include investi-gations of fluorescent chemosensors,activatable photosensitizers,mole-cularrecognition,andorganicfunctional materials.He was listedas a highly cited researcher inchemistry for 2014?2021.Fig.1(A)Chemical structures of 7-hydroxycoumari
40、n,fluorescein,andnew NIR fluorophore HDs bearing an optically tunable hydroxyl moiety.(B)Representative derivatives(16)of NIR fluorophore HDs.Chem Soc RevReview ArticlePublished on 10 February 2022.Downloaded by Dalian University of Technology on 2/21/2022 6:42:33 AM.View Article OnlineChem.Soc.Rev.
41、This journal is The Royal Society of Chemistry 2022chemiluminescence technology,positron emission tomography(PET),activatable photothermal therapy(PTT),activatable photo-dynamic therapy(PDT),and other applications Therefore,thesystematic and timely survey of the progress in this active researchfield
42、 is meaningful and urgent for the future development ofactivatableNIRfluorescentprobesbasedonhemicyanineplatformsfor detection,bio-imaging and therapeutics(Scheme 1).Thus,we believe that the discussion of the design approaches and bio-applications of activatable NIR fluorescent dyes based on thehemi
43、cyanine core in this review will receive wide attention andresearchers who want to use them in the field of activatablefluorescent materials can learn from this review.The first section of this review provides the history of thediscovery of hemicyanine fluorophores.Secondly,we havebriefly summarized
44、 the synthesis approaches of hemicyaninedyes and the design strategies of activatable fluorescent probes.Next,examples of fluorescent probes based on hemicyaninedyes for monitoring microenvironmental parameters,detectingions,sensing small molecules,tracking the activity of commonenzymes,and diagnosi
45、s and treatment of diseases are provided.Finally,the challenges and perspective of activity-based hemi-cyanine materials and their potential in clinical medicine arediscussed.2.Synthetic approaches of thehemicyanine scaffold and designstrategies of activity-based functionalprobesThe accidental disco
46、very of NIR hemicyanine fluorophores hasyielded an important platform for constructing multifunctionalactivatable fluorescent probes and drug delivery systems.53,58,7986Since this new class of NIR hemicyanine fluorophores werereported,synthetic methods related to their derivatives have beendeveloped
47、.Herein,we summarize the synthetic approaches ofseveral representative fluorophores,and other derivatives could beprepared based on these methods.As depicted in Fig.2A,in thepresence of a base,the chloro-substituted cyanine dye andresorcin in solution can be heated to obtain the target fluorophoredi
48、rectly.53The synthesis of an amino substituted hemicyaninescaffold(Fig.2B)or sulfur atom substituted cyanine dyes(Fig.2C)is similar to the previously mentioned method.It is not hard tosee that these strategies destroy classical cyanine dyes to constructnew fluorophore skeletons.However,the inflexibi
49、lity of thisdegradation method greatly limits the possibility of obtainingmore hemicyanine fluorophore derivatives.In contrast,the de novosynthesis strategy provides a wider scope for thepreparation of NIRhemicyanine derivatives,as shown in Fig.2D.53But,low yields anddifficulties in the preparation
50、of aldehyde derivatives would limitefficient expansion of the structures.To address the issue,Richardprovided a flexible de novo synthesis of NIR hemicyanine fluor-ophoresforsuccessfullyfosteringtheiruseas fluorogenicprobesin2015.87As shown in Fig.2E,an aldehyde was first obtained as a keyintermedia